Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calciphylaxis is a rare disorder of small-vessel calcification and cutaneous infarction associated with chronic renal failure. Rare cases of calciphylaxis not associated with chronic renal failure have been reported with breast cancer, hyperparathyroidism, and alcoholic cirrhosis. To our knowledge, we report the first case of calciphylaxis without chronic renal failure associated with cholangiocarcinoma and the first attempt to treat calciphylaxis with vitamin K. A 56-year-old woman presented with necrotic leg ulceration. She was treated initially with low-molecular-weight heparin, with no effect. A coagulation work-up showed vitamin K deficiency. During vitamin K therapy, the patient had fulminant progression of the calciphylaxis. She died, and an autopsy showed metastatic cholangiocarcinoma. Thrombosis and protein C deficiency have been implicated in the pathophysiology of calciphylaxis. Functional protein C deficiency may be one of several factors contributing to the development of calciphylaxis. Vitamin K therapy was ineffective in our patient and may have been detrimental.
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PMID:Calciphylaxis associated with cholangiocarcinoma treated with low-molecular-weight heparin and vitamin K. 1144 9

The potential for cyclo-oxygenase inhibition in cancer prevention and treatment is founded on epidemiology (reduction of colorectal cancer in aspirin users), animal experiments and molecular genetics. Trials using the NSAID sulindac also reduced the number of polyps in patients with familial adenomatous polyposis, but the well-known gastrointestinal toxic effects of aspirin and NSAIDs have discouraged the exploitation of their antineoplastic potential. The advent of specific COX-2 inhibitors, which do not interfere with the cytoprotective constitutive COX-1 enzyme, and the demonstration of increased COX-2 expression in many common malignancies beside colorectal cancer, has opened up new therapeutic possibilities. Recently a non-cyclo-oxygenase effect of COX-2 inhibitors, which combines the PPARdelta and the APC tumour suppressor activity, was also demonstrated. The selective COX-2 inhibitor celecoxib has been approved by the FDA for adjuvant treatment of familial adenomatous polyposis, and a large number of prevention and treatment trials of colorectal and other common cancers (prostate and breast cancer) have been started.
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PMID:COX-2 inhibition and prevention of cancer. 1156 43

Since the original identification of Wnt1 as a mammary oncogene in mouse mammary tumor virus infected mice, questions have been asked about its relevance to human breast cancer. Wnt1 is now known to be one of a large family of Wnt genes encoding structurally similar secreted signaling proteins, several of which are functionally redundant. The principal intracellular signaling pathway activated by these proteins has been elucidated in recent years. Components of this pathway include proto-oncogene products, such as beta-catenin, and tumor suppressor proteins such as APC. Although WNT1 itself has not been implicated in human breast neoplasms, it has been reported that other WNT genes are sometimes overexpressed in human breast cancer and there is growing evidence that downstream components of the Wnt signaling pathway are activated in a significant proportion of breast tumors.
Breast Cancer Res 2001
PMID:Wnt signaling in breast cancer: have we come full circle? 1173 84

Frizzled-related protein (Frp) is a new family of secreted proteins that contain a region homologous to the extracellular cysteine-rich domain (CRD) of the frizzled family proteins. The role of Frp protein is far from clear. To explore the role of Frp and its relationship to the Wnt-signalling pathway in breast cancer, in situ hybridization and immunohistochemical analyses of Frp, Wnt-1, APC, beta-catenin, and its target genes c-myc and cyclin D1 were conducted in 70 specimens of invasive ductal carcinomas of the human breast. Frp mRNA was down-regulated in 62 and elevated in eight tumour specimens, compared with adjacent normal tissues. In the course of tumour progression, however, Frp mRNA steadily increased in both tumour and the adjacent tissues. Interestingly, the number of cases with axillary lymph node metastasis was significantly lower in the group with elevated Frp than in the group with decreased Frp, suggesting that Frp may contribute as a prognostic factor in invasive breast cancer. Wnt-1, a gene implicated in human breast cancer, was markedly elevated in grade 1 tumours, but declined as tumour grade declined. The level of Wnt-1 was linearly correlated with its downstream target beta-catenin (p<0.05), but was inversely correlated with Frp (p<0.05), suggesting a possible negative regulatory role of Frp with regard to Wnt-1. APC was inversely correlated with beta-catenin (p<0.05). Beta-catenin, a key transcriptional activator responsible for the activation of both c-myc and cyclin D1 in colorectal tumours, was detected at high levels in the plasma membranes of cells in normal tissue. In tumour masses, however, beta-catenin lost its tight association with the membrane and diffused into the cytoplasm. Surprisingly, it clearly did not penetrate the nuclei, despite the fact that both c-myc and cyclin D1 were markedly elevated in all tumour tissues. As revealed in this study, Wnt-1/beta-catenin plays very different roles in the oncogenesis of breast and colon cancers. This first systemic analysis of the Frp and the Wnt-signalling pathway in human breast cancer provides a springboard for further work on the role of Frp in the development of breast cancer.
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PMID:Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours. 1179 65

The wealth of data in basic science and translational research may often represent a conundrum for clinical oncologists, who need to selectively consider this abundant information and translate it into therapeutic decisions. For the sake of simplicity, we have classified the multiplicity of genetic abnormalities in five repertoires that are rapidly assessable and useful for stratification in clinical trials: allelic imbalance, aberrant promoter methylation, gene mRNA overexpression, microtubule alterations, and polymorphisms. Allelic imbalance refers to chromosomal instability, which is a major feature of cancer, and innovative techniques used in colorectal cancer should also be implemented in lung cancer. Epigenetic changes (variations in transcription levels) have been extensively studied in non-small cell lung cancer. Methylation techniques have shown that these epigenetic changes commonly occur at the same frequency in numerous genes, both well-known ( FHIT, APC, p16 ) and recently discovered ( TMS1, RASSF1 ) in non-small cell lung cancer and in breast cancer. Innovative techniques like quantitative polymerase chain reaction can determine gene expression profiles, mainly overexpression of mRNAs, which may be related to resistance to specific cytotoxic drugs. In the near future, we hope these profiles can be used to individualize chemotherapy. Multiple microtubule alterations related to overexpression of different genes can also be used to predict response to taxanes and Vinca alkaloids. Finally, the assessment of polymorphisms could enable us to understand their functional consequences in chemotherapy response.
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PMID:Translational oncogenomics: toward rational therapeutic decision-making. 1188 Jul 7

To evaluate whether all-trans-retinoic acid (ATRA) is able to modulate the hemostatic system in patients with solid tumors, we studied patients with locally advanced breast cancer who were enrolled in a Phase Ib study of ATRA +/- Tamoxifen (Tam). In this study, two groups of 15 patients/each were treated for 21 days before operation with ATRA at three doses (15, 45, or 75 mg/m(2)/day on alternate days) given alone (group 1) or in combination with Tam (group 2). One additional group received Tam alone. Plasma samples were evaluated for hypercoagulation markers (FVIIa, F1+2, TAT, D-dimer), fibrinolysis proteins (t-PA, PAI-1), and coagulation inhibitors (protein C, AT). At baseline, cancer patients had FVIIa, F1+2, TAT, and PAI-1 significantly greater than control subjects. During treatment, in the patients given ATRA alone, hypercoagulation markers appeared unmodified. Instead, subjects given Tam alone had a significant elevation of FVIIa, F1+2, and TAT versus baseline. However, in the ATRA + Tam groups, hypercoagulation markers were decreased compared with Tam alone. These results suggest that in selected conditions, pre-operative ATRA may modulate the hypercoagulable state of breast cancer patients.
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PMID:Effect of all-trans-retinoic acid on the hypercoagulable state of patients with breast cancer. 1199 76

OBJECTIVES: Characterization of breast cancers by various tumour markers which are appropriate for the identification of high risk groups. Markers related to the metastasis cascade and tumour recurrence have been investigated. MATERIALS AND METHODS: RT-PCR was used to determine the expression of cytokeratin 20 in the bone marrow and sentinel lymph node of breast cancer patients (n=45). The expression of HER2, Cadherin E, Cyclin D, Bcl2 and Bax has been evaluated by Western blot (n=744 invasive ductal carcinomas and 117 invasive lobular carcinomas, 124 recurrent breast cancers). Mutations of p53, APC and beta Catenin genes were detected by PCR-SSCP method. RESULTS: Expression of cytokeratin 20 was found in 30% of the bone marrow samples indicating the presence of micrometastasis. The level of Cyclin D, HER2 and Bcl2 is elevated four-fold in the recurrent breast cancers. The metastasis of invasive ductal carcinomas is accompained by high frequency of p53 mutations (24%) and APC mutations (18%). The invasive lobular carcinomas could be characterized with low frequency of p53 mutation (3%), low level of Cadherin E and high level of catenin beta. CONCLUSIONS: Identification of micrometastasis can promote the development of therapeutic strategy. Evaluation of HER2 level and determination of p53 mutations contribute to the identification of high risk patients. Our results suggest that the progression of invasive ductal carcinomas depends on the APC mutations, while metastasis of invasive lobular carcinomas depends on beta catenin mutations.
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PMID:[Prognostic factors of breast cancer] 1205 Jul 67

Members of protein kinase C (PKC) family have been widely implicated in the regulation of cell proliferation, differentiation and survival. Increased protein C activity in malignant breast tissue and in most aggressive breast cancer cell lines suggests possible role of PKC in the development and progression of breast cancer. PKC may be therefore a target for breast cancer treatment. In our study we attempted to investigate the effect of: phorbol ester (PMA)-PKC activator, and bisindolylmaleimide II (GF II), a highly selective PKC inhibitor, on the proliferation as well as induction of apoptosis and necrosis in breast cancer cell line MDA-MB-231. Our results provide evidence for multidirectional effects of PKC on the proliferation of this type of breast cancer cells. The effects of both compounds were different after short time of exposition (1-3 h). PMA induced proliferation, while GF II showed an opposite effect. After 24 h, however, both compounds exhibited relatively high inhibitory effect on the proliferation and proved to be effective in induction of necrosis and apoptosis.
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PMID:Protein kinase C involvement in proliferation and survival of breast cancer cells. 1205 41

Linoleic and alpha-linolenic acids, obtained from plant material in the diet are the precursors in tissues of two families with opposing effects which are referred to as "essential fatty acids" (EFA): arachidonic acid (AA) and pentaene (eicosapentaenoic acid: EPA) and hexaene (docosahexaenoic acid: DHA) acids. The role of EFA is crucial, without a source of AA or compounds which can be converted into AA, synthesis of prostaglandins (PGs) by a cyclooxygenase (COX) enzyme would be compromised, and this would seriously affect many normal metabolic processes. COX, also known as prostaglandin endoperoxide synthase (Pghs) or as prostaglandin G/H synthase, is a key membrane bound enzyme responsible for the oxidation of AA to PGs. Two COX isoforms have been identified, COX-1 and COX-2 that form PGH2, a common precursor for the biosynthesis of thromboxane A2 (TxA2), prostacyclin (PGI2) and PGs (PGD2, PGE2, PGF2alpha. COX-1 enzyme is expressed constitutively in most cells and tissues. Its expression remains constant under either physiological or pathological conditions controlling synthesis of those PGs primarily involved in the regulation of homeostatic functions. In contrast, COX-2 is an intermediate response gene that encodes a 71-kDa protein. COX-2 is normally absent from most cells but highly inducible in certain cells in response to inflammatory stimuli resulting in enhanced PG release. PGs formed by COX-2 primarily mediate pain and inflammation but have multiple effects that can favour tumorigenesis. They are more abundant in cancers than in normal tissues from which the cancers arise. COX-2 is a participant in the pathway of colon carcinogenesis, especially when mutation of the APC (Adenomatous Polyposis Coli) tumour suppressor gene is the initiating event. In addition, COX-2 up-regulation and elevated PGE2 levels are involved in breast carcinogenesis. It seems that there is a correlation between COX-2 level of expression and the size of the tumours and their propensity to invade underlying tissue. Inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) of COX enzymes which significantly suppress PGE2 levels, reduced breast cancer incidence and protected against colorectal cancer. Therefore it is suggested that consumption of a diet enriched in n-3 PUFA (specifically EPA and DHA) and inhibition of COX-2 by NSAIDs may confer cardioprotective effects and provide a significant mechanism for the prevention and treatment of human cancers.
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PMID:Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. 1219 20

Tamoxifen reduces breast cancer incidence among healthy women, but is associated with an increased risk of venous thrombosis. We studied the 6 month effects of tamoxifen on venous thrombosis risk factors in women without cancer. One hundred and eleven women at one centre who were participants in a multicentre breast cancer prevention trial were randomized, in double-blind fashion, to receive 20 mg/d of tamoxifen or placebo. The activated protein C (APC) ratio and concentrations of antithrombin, protein C antigen, and total protein S were measured at baseline and 6 months of treatment. None of the factors changed over 6 months in placebo-treated women. Among tamoxifen-treated women, antithrombin and protein S, but not protein C or APC ratio were reduced. Sequential antithrombin concentrations with tamoxifen were 114% and 104% (P = 0.001 compared with placebo). Sequential protein S concentrations with tamoxifen were 18.42 and 17.30 micro g/ml (P = 0.02 compared with placebo). Reductions in antithrombin and protein S were greater in postmenopausal women, but did not differ by other risk factors for venous thrombosis, such as body mass index. Reductions of antithrombin and protein S, but not protein C or APC resistance, might relate to the increased risk of venous thrombosis associated with tamoxifen treatment.
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PMID:Effect of tamoxifen on venous thrombosis risk factors in women without cancer: the Breast Cancer Prevention Trial. 1249 85


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